Becoming a posada along the trade route between colonial Buenos Aires and Córdoba, the settlement was given its name on 3 January 1626, for the parchment paper (document lost by a group of Spaniards) found there and conforming to an Araucanian term meaning "red soil.

The fort played a prominent role during the initial battles in the war for independence and, in 1815, was the site of a mutiny led by Col. Ignacio Álvarez Thomas against the fledgling nation's Head of State, Director Carlos María de Alvear.

Col. Álvarez Thomas' coup d'état against Director de Alvear's brief though highly divisive autocracy averted the dissolution of the United Provinces of the River Plate, the confederacy that later became Argentina.

[2] Following Governor Rosas' 1852 overthrow, the local gentry allied themselves to Bartolomé Mitre, a prominent advocate on behalf of Buenos Aires Province for greater autonomy.

President Mitre's 1862 establishment of Argentina's first institute of Agronomy helped lead to the development of a new economic activity in the region around Pergamino: intensive agriculture.

[4] Pergamino's population, now mostly European immigrants and their children, nearly tripled to almost 30,000 between 1895 and 1914; this era saw the establishment of important Basque, Piemontese, Provençal and Lebanese communities, as well as the inauguration of the Hotel Roma in 1913, one of the best-known Art Nouveau structures in the area.

[2] Another native of Pergamino, Héctor Chavero, became nationally renowned during that era after releasing an album of folklore ballads and narration, El payador perseguido ("The Persecuted Troubadour"); by then, he was known by his pseudonym, Atahualpa Yupanqui and has remained, long after his death in 1992, arguably the most influential musician of his genre in Argentina.

One of Pergamino's Lebanese immigrants, Isaac Annan, established the city's first garment factory during the late 1940s, creating Far West Jeans and Manhattan Shirts, two of Argentina's best-known domestic clothing brands.

[6] Serious floods in 1939, 1975, 1984 and 1995 underscored the need for more investments in infrastructure and by 2002, the combined effects of a wave of imports and an acute economic crisis led to the closure of most of Pergamino's industries and many of its retail establishments; the textile industry, in particular, was reduced to about 600 workers;[11][12] amid rising unemployment, crime rates and general pessimism, one of the most notable achievements in that difficult era was the establishment of the Pergamino Regional University, the city's first institution of higher learning, in 1993.

The school was absorbed into the National University of Northwestern Buenos Aires upon that latter entity's creation in 2002, and its Pergamino campus today enrolls about 500 students yearly.

Elected in 1999, he has capitalized on the city's economic recovery by emphasizing public works and in 2005, successfully lobbied the Administration of President Néstor Kirchner for a 180 km (112 mi) extension of the Route 8 expressway into Pergamino, a long-overdue improvement for one of the nation's most-transited stretches of two-lane road.